Project Portugal 2030

Summary

Viral infections are one of the most prominent and persistent threats to human health, resulting in high mortality rates and having a tremendous impact on the economy. The frequent mutations and emergence of new viral species undermine a large part of the existing therapeutics, which are typically directed at specific viruses or strains, and emphasize the importance of the discovery of novel broad-spectrum antiviral combat strategies. The basis for such therapeutics may be uncovered by investigating common mechanisms shared by different viruses, e.g. as part of their interaction with the host cells’ machinery. In recent years, PO have emerged as antiviral and pro-viral platforms in the context of viral infections. Although different viruses of different families and origins are reported to modulate PO biogenesis and/or metabolism to either counteract the cellular antiviral response or promote virus particle formation and propagation, research progress in this field has been slow and fragmented, mainly because: i) for most viruses only few specific PO-related mechanisms and infection stages have been analysed; ii) several studies report opposing findings, possibly related to the different phases of infection investigated; iii) most of the studies were performed by virology groups, with little or no expertise in PO biology. To overcome these issues, a structured and systematic approach is needed to study this virus-PO interplay, incorporating i) different viruses, ii) analysis during different phases of the infectious cycle, and iii) a multidisciplinary team that combines expertise in both virology and PO biology. PERseVIR will therefore execute systematic studies with different viruses (IAV, coronaviruses and YFV), to identify shared anti- or pro-viral PO functions and PO-mediated mechanisms that can be used as leads for developing host(PO)-directed specific and/or broad-spectrum antiviral strategies. We have defined the following research objectives: i) To elucidate how different types of viruses manipulate PO or PO functions to enhance viral propagation ii) To identify how PO, in concert with other organelles, generate an effective immune response against different types of viruses iii) To devise novel PO-targeted antiviral strategies that may be used as leads for development of host-directed therapies against specific viruses, or, ideally, against viruses from different families Although ambitious, our aims and hypotheses are supported by strong preliminary data and a uniquely positioned research team. By combining expertise on PO biology with expertise on virology and immunology, and using a variety of state-of-the-art biochemical, genetic, virological, immunological, molecular and cell biological approaches and technologies combined with bioinformatics, PERseVIR is optimally equipped to shed a unique light on the interactions between viruses and PO. With the proposed set of experiments and the combination of expertise of the team members, we will go well beyond the state-of-the-art and produce several unique results of high societal value. By employing complementary perspectives and methodological approaches to address the interplay between PO and different viruses, PERseVIR will discover novel cellular targets that can further be exploited for the development of specific and/or broad-spectrum antiviral therapeutics.